Human Molecular Genetics, 2002, Vol. 11, No. 5 499-505
© 2002 Oxford University Press
Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, B.P. 163, 67404 ILLKIRCH Cedex, C.U. de Strasbourg, France, 1Societé Neurofit, SA 67404 ILLKIRCH Cedex, C.U. de Strasbourg, France and 2Zentrum für Molekulare Neurobiologie, Martinistrasse 52, D 20246 Hamburg, Germany
Received October 3, 2001; Revised and Accepted January 4, 2002.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSSciatic nerve pathologyCNS pathologyDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Adrenomyeloneuropathy (AMN) and cerebral childhood adrenoleukodystrophy (CCALD) are the main phenotypic variants of an X-linked inherited metabolic disorder causing demyelination, X-linked adrenoleukodystrophy (X-ALD). It is caused by mutations in the ABCD1 (ALD) gene encoding a peroxisomal ABC transporter. Inactivation of the murine ALD gene does not lead to a detectable clinical phenotype in mice up to 6 months, and no cerebral pathology resembling the childhood form (CCALD) was observed. In this work, we show that older ALD-deficient mice exhibit an abnormal neurological and behavioral phenotype, starting at around 15 months. This is correlated with slower nerve conduction, and with myelin and axonal anomalies detectable in the spinal cord and sciatic nerve, but not in brain. The phenotype of ALD-deficient mice mimics features of human AMN, thus providing a model for investigating the pathogenesis of this disease.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSSciatic nerve pathologyCNS pathologyDISCUSSIONMATERIALS AND METHODSREFERENCES |
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X-linked adrenoleukodystrophy (X-ALD: McKusick no. 300100) is a metabolic genetic disorder characterized by progressive demyelination within the CNS, adrenal insufficiency and accumulation of saturated very long chain fatty acids (VLCFAs) due to their impaired ß-oxidation in peroxisomes. It is one of the most frequent peroxisomal disorders with a minimum incidence of 1 in 21 000 males (1). The phenotypic presentation differs widely, even within the same kindred. The cerebral demyelinating form of ALD (CCALD) affects boys between 5 and 12 years of age (35% of all ALD cases), and evolves to a vegetative stage or death within 2 to 5 years. It is associated with a strong inflammatory reaction in the CNS white matter and may involve autoimmune mechanisms. The adult form, adrenomyeloneuropathy (AMN), appears to be the most common phenotype (2). The mean age at onset of AMN is 28 ± 9 years. It involves mainly the spinal cord and often peripheral nerve in the form of distal axonopathy, and presents with slowly progressive stiffness and weakness of legs and sphincter disturbances. In contrast to CCALD, AMN has little or no inflammatory component, and may be often misdiagnosed as multiple sclerosis or spastic paraparesis. The absence of an apparent genotype–phenotype correlation suggests the influence of modifier genes and/or environmental precipitating factors. For a review see (3).
The disease is caused by mutations in the ALD gene (official nomenclature ABCD1) that lead to loss of function of the ALD protein (ALDP) (4). ALDP is an ATP-binding cassette (ABC) half-transporter that is an integral peroxisomal membrane protein (5). The exact function of ALDP is unknown, but might be involved in the transport of VLCFAs into the peroxisome by analogy to its yeast homologs Pxa1p and Pxa2p (6,7).
Mice lacking ALDP have been generated by homologous recombination by three different laboratories (8–10). These mice did not present a detectable clinical phenotype up to at least 6 months of age, in spite of an accumulation of VLCFAs in tissues similar to that found in X-ALD patients.
In the present work, we report that ALDP-deficient mice develop a late onset phenotype that appears comparable to AMN, with abnormal myelin and axonal loss in both spinal cord and sciatic nerve.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSSciatic nerve pathologyCNS pathologyDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Behavioral and neurological phenotype of the ALD-deficient mice
The generation and characterization of the ALD knock out (KO) mice has been described in detail (8). These mice did not show an abnormal behavioral or neurological phenotype up to at least 6 months of age (9) (K.D.Smith, personal communication). Here we analyzed older animals (at 15 and 20 months of age), to investigate whether mutant mice develop a late-onset phenotype. Home cage behavior of ALD KO was indistinguishable from that of wild-type littermates, and there were no obvious signs of motor incoordination, ataxia or other apparent neurological abnormalities. Since AMN patients present often only mild deficits in psychomotor speed and executive functions, we challenged the KO mice with a battery of behavioral/motor tests.
To investigate the motor coordination ability of ALD mice, a rotarod test was performed on 15- and 20-month-old animals. Indeed, ALD KO mice on a mixed 129Sv/C57B6 genetic background showed no significant impairment of their rotarod performance at the age of 6 months, as described previously (9). At the age of 15 months, there was still no difference in performance between the two groups. On the contrary, at 20 months of age, ALD mutants showed a severe impairment in their performance, as they fell off the rotarod in less than 20 s on average (Fig. 1A).
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To assess further the motor activity of ALD-deficient mice, the animals were examined in the open field mobility paradigm. This test is used to study novelty-induced exploratory activities and mobility in a general manner. Repeated-measures ANOVA indicated a significant difference between ALD KO and controls only for the first interval of testing (first 5 min) at 15 months of age (Fig. 1C, P < 0.01). This result indicates that only the initial spontaneous motor activity of ALD-deficient mice was reduced. However, at 20 months of age, a significant reduction of exploratory activities or hypoactivity during all the testing period was evident for mutant animals (Fig. 1D, P < 0.0001).
Another interesting difference between wild-type and mutant animals was noted when rearing behavior in the open field (OF) was quantified. ALD mutants exhibited significantly fewer episodes of this behavior than wild-type mice both at 15 and 20 months of age (Fig. 1B, unpaired Student’s t-test). We found no significant difference in gait pattern between the two groups of mice both at 15 and 20 months of age (data not shown).
Nerve conduction studies were performed at 15 and 20 months of age (Table 1). When compared to their control littermates, ALD-deficient mice exhibited a significant increase of compound muscle action potential (CMAP) latency already at 15 months of age (unpaired Student’s t-test, P < 0.01), which was even more severe at 20 months of age (P < 0.001). CMAP is representative of fast conducting, mostly motor fibers. Slowing of sensitive nerve conduction velocity (SNCV) also appeared at the oldest age tested. Interestingly, CMAP amplitude remained unaffected suggesting myelin abnormalities rather than important axonal loss.
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Sciatic nerve pathology |
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Light and electron microscopy of sciatic nerves revealed myelin and axon abnormalities [n = 4 animals for each genotype (wild-type, mutant), and age (16, 21 months)]. Although signs of acute demyelination were not seen, axons with abnormally thick and disorganized myelin sheaths were encountered at 16 months, suggesting focal hypermyelination (Fig. 2B). These myelin thickenings of closely apposed loops of redundant, normally spaced myelin, resemble myelin tomacula (11), and were predominantly infoldings of myelin loops surrounding the corresponding axons (Fig. 2B–E). Formation of onion bulbs was not detected in mutant nerves of either age. Schwann cell processes were enlarged and contained myelin-like figures, as well as fibrillar and paracrystalline osmiophilic inclusions (data not shown). In human patients, the characteristic lamellar and lamellar-lipid inclusions typical of ALD may be found within Schwann cell cytoplasm, or within endoneurial macrophages. No lamellar-lipid inclusions were detected in occasionally encountered macrophages (Fig. 2F).
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CNS pathology |
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TOPABSTRACTINTRODUCTIONRESULTSSciatic nerve pathologyCNS pathologyDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In the adult mouse and human CNS, ALDP is expressed in astrocytes, microglial cells and oligodendrocytes, but not in neurons (12). Hemotoxylin and eosin, PAS and Luxol-fast blue stains of brain and cerebellum from 16- or 21-month-old mutants failed to reveal any infiltrates of immune cells, vacuolar degeneration or myelin loss (data not shown). In oligodendrocytes, ALDP is restricted to subpopulations located in the corpus callosum, internal capsule and anterior commisure, regions that are first affected in the disease (12). Examination of semithin and ultrathin sections of these fiber tracts did not reveal any obvious pathological features (data not shown).
Semithin sections from cervical, thoracic and lumbar regions of spinal cords of wild-type and mutant littermates were also compared [n = 4 animals for each age (16 and 21 months) and genotype]. At low magnification, mutant gray matter appeared indistinguishable from wild-type whereas white matter showed some focal abnormalities. Such abnormal features included myelinated fibers presenting redundant myelin sheaths, and degenerating axons (Fig. 3B–G). As seen in Figure 3G, electron microscopic analysis revealed pockets of severe ultrastructural aberrations of both axons (as recognized by their unusually electron-dense cytoplasm, their small calibre and the disappearance of organelles and other cytoplasmic components, arrow) and myelin (redundant sheaths that do not contact the axons, asterisks).
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Macrophages/microglia engulfing myelin debris, similar to that found in PNS, and occasionally containing fibrillar deposits of lipidic materials and paracrystalline, spicular needle-like inclusions (Fig. 3H), were encountered.
Morphometric studies were performed on Toluidine blue-stained semithin (1 µm) cross-sections of sciatic nerves and spinal cord. Quantitation of the proportion of total number of myelinated fibers versus fibers with myelin sheaths of irregular thickness, lacking axons (altered fibers, see Fig. 4) revealed a significant effect due to the ALD gene inactivation, already visible at 16 months of age.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSSciatic nerve pathologyCNS pathologyDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Based on behavioral, morphological, morphometric and clinical data, we present evidence in this study that ALD-deficient mice develop a late onset, progressive neurodegenerative phenotype. Main features identified are myelin alterations and axonal degeneration in spinal cord, and a peripheral neuropathy with histological signs and clinical symptoms (EMG) indicative of myelin and axonal damage. Thus, a door is open to the experimental study of the mechanisms leading to axonal loss and myelin alterations due to this particular type of metabolic stress.
A matter of controversy in the AMN field is the question whether axonal degeneration is secondary to or precedes myelinopathy. An electrophysiological study of peripheral nerves in 23 AMN patients led to the conclusion that the changes observed in these patients are related to primary axonal degeneration (2). Other studies favored a mixture of axonal loss and multifocal demyelination (13) or a rather primary myelin involvement affecting latencies rather than amplitudes of waves (P.Sokolowski and W.Köhler, personal communication). Our electrophysiological and histological data from sciatic nerves favor a mixture of myelin and axonal involvement (hypermyelination, axonal atrophy) at least at early stages of pathology in the mouse.
In mutant spinal cords, we identified consistently axonal degeneration, comparable to the pathological lesions in AMN patients. In man, cervical gracile and lumbar corticospinal tracts usually are most severely affected, and these tracts demonstrate comparable losses of both axons and myelin (14).
The myelin abnormalities observed in peripheral nerves show similarities with those observed in humans and mice with mutations affecting myelin components. Focal hypermyelination in the form of myelin tomacula (11) is observed in patients with deletion of one allele of PMP22 [hereditary neuropathy with liability to pressure palsies (HNPP)]. PMP22, P0 and MBP have been postulated to control myelin thickness and myelin integrity. In MAG and PMP22-deficient mice, the degeneration of axons is possibly linked causally to the occurrence of myelin tomacula, since axons surrounded by these hypertrophic myelin profiles often show a compressed appearance (15,16). The view that hypermyelination may cause axonal damage is in line with the finding that in P0 KO mice, only axons associated with unusually thick myelin sheaths degenerate (17). Alternatively, axonal shrinkage due to chronic atrophy could result in myelin sheath collapse and tomaculi formation (18). Whether degenerating axons associated with myelin tomacula suffer from a physical constriction of the axon leading to impaired transport of neuronotrophic or other vital components remains an open question.
A follow-up of the progression of the clinical abnormalities of the ALD-deficient mice is required to further assess the evolutive nature of axonal degeneration and myelin abnormalities. Studies of phospholipid bilayers enriched in VLCFA suggest that incorporation of VLCFAs might destabilize membranes (19) and, in particular, the multilamellar membrane structure of myelin (20). However, accumulation of VLCFAs alone is not sufficient to cause demyelination, since patients with similar biochemical perturbations (assessed by levels of VLCFAs in serum or fibroblasts) can present very different phenotypes or age at onset of the disease.
The ALD-deficient mouse is a valuable model for drug and gene delivery approaches to therapy. Its long life-span may allow follow-up of clinical and histological pathology and evaluation of the desirable long-lasting curative effects. For instance, the pharmacological compound 4-phenylbutyrate (4PBA) has shown its efficacy to reduce the accumulation of VLCFAs in brain and adrenals of these mice after 4 to 6 weeks of dietary treatment (21). Thus, it would be of interest to monitor the effect of the drug on the neurodegenerative features described in the present work. Since the peripheral nerve is affected, preliminary pharmaceutical interventions even with compounds that are not proven to cross the blood–brain barrier could be envisaged. Indeed, Lorenzo’s oil has been reported in one study to exert a positive effect on peripheral nerve conduction of AMN patients although it does not ameliorate or prevent central demyelination (22), presumably because it does not penetrate into the CNS (23,24).
In summary, the importance of our observations is 3-fold: (i) they link ALD gene inactivation to myelinopathy and axonal degeneration in mice; (ii) they offer a system in which the cascade of events preceding pathology can be studied; and (iii) they provide a model in which therapies can be assessed.
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MATERIALS AND METHODS |
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Animals
The generation of ALD-deficient mice on a pure 129Sv background has been described (8). They were backcrossed for two generations with inbred C57BL/6J wild-type mice. The resulting generation was intercrossed, and mice homozygous for the ALD deficiency and their wild-type littermates were obtained on a mixed 129Sv/C57BL/6J background. Genotyping was done by PCR basically as described by Lu et al. (8). Histology, morphometry, behavioral testing and electrophysiological experiments were performed in a blind way with respect to the animal’s genotype.
Behavioral testing
The following tests were performed with naive ALD-deficient mice and wild-type littermate controls.
Rotarod test
We used a rotarod apparatus from Bioseb, Paris, France; diameter of the axis was 3 cm. The animals were trained 2 days before the day of the test. They were placed on the rotarod with an initial speed of rotation of 4 r.p.m. that was progressively increased to 10 r.p.m. (in 2 min). When the rotarod speed reached 10 r.p.m., we recorded the time until the mice fell off the rotarod. The test was stopped arbitrarily at 180 s. Three trials per animal were recorded and the mean was taken as characteristic value.
Footprint analysis
Gait parameters of ALD-deficient mice were compared with those of non-transgenic mice by appraising footprint patterns. The rear paws of knock out mice and wild-type controls were inked, and the mice were allowed to walk through a tunnel with a piece of paper on its floor. The resulting footprint patterns were assessed quantitatively by three measurements: step length, gait width and intrastep distance.
Locomotor activity in open field
A video track was placed over a plexiglass (OF) (52 x 52 cm; height, 40 cm) and recorded the activity of the animals during 15 min. The floor of the OF was divided into nine equal squares. Square crossing, rearing and the location of the mouse (middle, wall, corner) were registered under video control. Prior to these tests, mice were adapted in a quiet room under red light illumination.
Electrophysiological recordings
Electromyographical (EMG) recordings were performed using a Neuromatic 2000M electromyograph (Dantec, Les Ulis, France). Mice were anaesthetized with intraperitoneal injection of 60 mg/kg ketamine chlorhydrate (Imalgène 500®, Rhône Mérieux, Lyon, France).
CMAP and distal latency were recorded in the gastrocnemius muscle after stimulation of the sciatic nerve. A reference electrode and an active needle were placed in the hindpaw. A ground needle was inserted on the lower back of the mouse. The sciatic nerve was stimulated with a single 0.2 ms square pulse at a supramaximal intensity (12.8 mA). The amplitude (mV) and the latency of the motor wave were recorded.
SNCV was also recorded. The tail skin electrodes were placed as follows: a reference needle inserted at the base of the tail and an anode needle placed 30 mm away from the reference needle towards the extremity of the tail. A ground needle electrode was inserted between the anode and reference needles. The caudal nerve was stimulated with a series of 20 pulses (for 0.2 ms) with an intensity of 12.8 mA. The average conduction velocity was calculated.
Histology
Mice were anaesthetized by IP injection of 100 mg/kg Imalgène 500®Rompun. Sciatic nerve, spinal cord and brain were fixed overnight with a 4% PFA and 3% of glutaraldehyde (Fluka, St Quentin Fallavier, France) in phosphate buffer (pH 7.4, 0.1 M) solution. Tissue was postfixed for 1 h in 1% osmium tetroxide in phosphate buffer, dehydrated in serial ethanol solutions and embedded in an araldite-epon mixture. Embedded tissues were then placed at 60°C for 2 days to polymerize. Transverse semithin sections, 1 µm in thickness, were prepared with an ultramicrotome and stained with toluidine blue. Ultrathin sections (50 nm) were observed on Philips C12-208 electron microscope.
Morphometry
Morphometric analysis of sciatic nerves and spinal cords was performed using the Image Proplus software (Mediacybernetics, Silver Spring, MD). Fields were chosen randomly, from sections taken from the proximal 5 mm portion of sciatic nerves and L4-L5 level of spinal cords tissue. Three semithin sections of each tissue and animal were analyzed and three fields per section were studied. Myelinated fibers without axons, redundant myelin and fibers showing sheaths with too large thickness in respect to axonal diameter were scored as ‘altered fibers’.
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ACKNOWLEDGEMENTS |
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We are indebted to Drs P.Aubourg, P.Sokolowski, W.Köhler and M.E.Stoeckel for fruitful discussions. ALD mutant mice on the 129Sv background were a kind gift of Dr Kirby Smith (KKI, Baltimore, MD). We thank M.Gendron and C.Kretz for priceless technical assistance; M.le Meur, E.Metzger and staff at the IGBMC animal facility for mouse care. This study was supported by funds from the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpital Universitaire de Strasbourg (HUS) and the CEE program ‘Adrenoleukodystrophy Concerted Action’ (contract no. BMH4-CT96-1621), the Association Française contre les Myopathies and the European Leukodystrophy Association. A.P. was a fellow of EMBO, the ‘Training and Mobility’ Research Program of the CEE and Fondation pour la Recherche Médicale.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +33 3 88 65 32 44; Fax: +33 3 88 65 32 46; Email: apujol@igbmc.u-strasbg.fr
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M. Asheuer, I. Bieche, I. Laurendeau, A. Moser, B. Hainque, M. Vidaud, and P. Aubourg Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy Hum. Mol. Genet., May 15, 2005; 14(10): 1293 - 1303. [Abstract] [Full Text] [PDF]
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I. Oezen, W. Rossmanith, S. Forss-Petter, S. Kemp, T. Voigtlander, K. Moser-Thier, R. J. Wanders, R. E. Bittner, and J. Berger Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency Hum. Mol. Genet., May 1, 2005; 14(9): 1127 - 1137. [Abstract] [Full Text] [PDF]
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A. Pujol, I. Ferrer, C. Camps, E. Metzger, C. Hindelang, N. Callizot, M. Ruiz, T. Pampols, M. Giros, and J. L. Mandel Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy Hum. Mol. Genet., December 1, 2004; 13(23): 2997 - 3006. [Abstract] [Full Text] [PDF]
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A. K. Heinzer, P. A. Watkins, J.-F. Lu, S. Kemp, A. B. Moser, Y. Y. Li, S. Mihalik, J. M. Powers, and K. D. Smith A very long-chain acyl-CoA synthetase-deficient mouse and its relevance to X-linked adrenoleukodystrophy Hum. Mol. Genet., May 15, 2003; 12(10): 1145 - 1154. [Abstract] [Full Text] [PDF]
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 A. K. Heinzer, S. Kemp, J.-F. Lu, P. A. Watkins, and K. D. Smith Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy J. Biol. Chem., August 2, 2002; 277(32): 28765 - 28773. [Abstract] [Full Text] [PDF]
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